Erratum in

Abstract

Behavioral variant frontotemporal dementia (bvFTD) erodes complex social-emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region-specific neuronal targets in early bvFTD.

Human area FI. (A) Low magnification tracing illustrates the FI's position: ventral to the dorsal (dysgranular) anterior insula (dAI) and posterolateral to the posterior orbital gyrus (POrbG), which sits rostral to FI across the circular insular sulcus. Layer 5 ROIs (not shown) were traced for VEN, fork cell, and layer 5 neighboring neuron counting. To visualize the spatial distribution of VENs (pink diamonds) and fork cells (blue triangles), exhaustive mapping was performed for a single representative section from the control subject with the median VENs + Fork cells/Total neurons. Results are shown at increasing magnification in (A–D). (B) Separate and merged VEN and fork cell maps show that VENs predominate within the lateral and medial domes, whereas fork cell density increases within the long thin belly of the FI. A portion of this belly is magnified in (C) to reveal that fork cells occupy a more superficial position within layer 5, whereas VENs extend deep into layer 5b. Within areas of gyral curvature (D), VENs and fork cells cluster together within large radial columns (gray lines drawn through center of each column to suggest radial architecture). Cl, claustrum; Put, putamen.

Correlations between VEN and fork cell losses in bvFTD. FI VEN and fork cell losses showed significant correlations both between (A, B) and within the hemispheres (C, D) but only the correlation between right VENs and right fork cells met a stringent (Bonferroni-corrected) significance threshold. All axis values represent percentage of the control group median.

Correlation between VEN and fork cell losses and anatomical, functional, and behavioral deficits. (A) VEN and fork cell losses, especially on the right, correlated significantly with atrophy severity (Broe stage) in bvFTD. Mean (left/right) VEN and fork cell loss is plotted against Broe stage to illustrate the relationship between the 2 cell types. (B) In bvFTD, functional severity (CDR–SB) correlated with VEN loss in the right FI but not in the left. Across bvFTD and AD, a combined index of right VEN and fork cell loss significantly correlated with peak overall behavioral symptom severity (NPI Total, C) and disinhibition (D). Left-sided correlations with behavioral symptoms did not survive a stringent (Bonferroni-corrected) significance threshold.